Novel Methacrylate-Thiol-Ene Composites for Dental Restorative Materials. As the demand for aesthetically pleasing restorative materials has increased, so has the desire and demand for improved performance. Despite their increasing prevalence, the resin phase of these materials has remained largely unaltered since Bowen first proposed the materials nearly 50 years ago. Presently, composites suffer from shrinkage and stress that arise during polymerization, a subsequent lack of appropriate mechanical properties of the resin material, and low depth of cure for polymerization. The composites also contain in their core monomer the substitutent bisphenol-A, which is associated with ever increasingly significant regulatory and health concerns. Following polymerization, the composites also contain significant fractions of unreacted monomer that results in the critical presence of extractables that coupled with moisture uptake by the sample can lead to degradation. The result is often secondary cavities and premature failure where composites average lifetime is less than 8 years. Classically, the limitations of these materials have involved a trade-off between the mechanical behavior, the stress and the extent of reaction/conversion of the material that limits extractables and water sorption. The BisGMA/TEGDMA system has proven to be a local optimum within this overall flawed compromise. Here, we propose a novel methodology that changes the reaction paradigm and allows for improvement in each of these critical areas - lower shrinkage and stress, improved mechanics, higher extent of reaction, improved depth of cure along with the elimination of bisphenol-A, and reduced extractables and degradation. An approach using thiol-ene click reactions and monomers is combined with an improved methacrylate approach to yield dramatic improvements in each of these critical areas. Within the two aims of this work, two distinct elements of the formulation are targeted - development and optimization of the resin phase, and development and optimization of the filler/filler coupling agent combination. While both of these aims can proceed independently and will yield valuable results in and of themselves. The synergistic combination of these approaches will forge an entirely new composite dental restorative with expected improvements in conversion, reduced degradation and improved biocompatibility and public safety, mechanics and service life. Specifically, in the first aim, we seek to incorporate urethane-based methacrylates in place of bisphenol-A based monomers. The increased refractive index of the thiol-ene components enables the use of non-bisphenol-A-based monomers - with corresponding benefits of enhanced material properties. Thus, the increased urethane content will result in both improved material properties and reduced shrinkage stress as compared to utilizing BisGMA or BisEMA as the methacrylate in methacrylate-thiol-ene formulations. Second, we propose to focus on the comprehensive development of an integrated filler system that is improved overall and designed specifically for integration with the methacrylate-thiol- ene resins. Our preliminary results have demonstrated a much greater mechanical property enhancement in composite methacrylate-thiol-ene systems than in the control composite BisGMA/TEGDMA systems. These results indicate that the increased conversion of methacrylate-thiol-ene systems will not only dramatically reduce the amount of extractable monomer but also enhance the interaction between the resin phase and the fillers, leading to enhanced mechanical properties. This same benefit is expected to lead to improved adhesion with the native tooth structure. The proposed aims are predicated on the hypothesis that appropriate materials synthesis and subsequent incorporation of urethane-methacrylate base components, optimization of the formulation composition and polymerization mechanism, and optimally designed and modified fillers will improve dental composites through dramatic reductions in shrinkage stress, improvement in composite mechanical properties, moisture uptake and reduced extractables along with improved toxicity and implementation of BPA-free formulations. Results to date demonstrate improved polymerization rates, volume shrinkage induced stress, mechanical properties, depth of cure, oxygen inhibition, toxicity and final conversion. These results will for dental composite systems with enhanced longevity and improved clinical scope. The methacrylate-thiol-ene technology was developed at the University of Colorado by Drs. Cramer and Bowman with funding from an NIH R01 grant (DE018233 - Development of Novel Thiol-Ene-Methacrylate Composites for Dental Restorative Materials). In total, the prior work supported in this area by the R01 grant, of which the PI for this proposal was a co-PI, resulted in 17 peer reviewed publications and two US patents that have been optioned by Colorado Photopolymer Solutions (CPS). Drs Cramer and Bowman have previous experience developing and commercializing dental restorative materials through their collaboration with Septodont Confi-Dental products. During this collaboration, a novel methacrylate formulation from University of Colorado was licensed by Septodont Confi-Dental Products Division and is available commercially as N'Durance (http://www.septodontusa.com/products/n-durance). This provides us with first-hand knowledge for the testing and procedures necessary to commercialize a dental restorative material as well as a potential partner for Phase III. CPS has significant experience in both dental materials and (meth)acrylate and thiol-ene materials. CPS has recently developed and licensed two orthodontic adhesives (Perfect-A-Smile and Bond Aligner) that are currently commercially available through Reliance Orthodontic Products (www.relianceorthodontics.com). CPS also develops and manufactures a range of (meth)acrylate and thiol-ene based formulations for adhesives, optical materials, and other specialty applications.